The oral route of administration is considered as the most widely accepted route because of its convenience of self-administration, compactness and ease of manufacturing. Oral pharmaceutically accepted formulations, viz., liquid, pills, tablets, etc. generally include a multitude of ingredients, one or more of which are typically “active” ingredients. A pharmaceutical active ingredient is a substance having a specific physiological action and effect with minimal or no side effects. Thus, active ingredients are generally targeted for the treatment of specific symptoms, ailments, diseases, or disorders related to the body. Non-active ingredients, such as lubricants, colorants, flavoring agents, texture modifiers, disintegrants, preservatives, among others, generally referred to as “excipients”, are commonly included with the active ingredient(s) to render the composition desirable in terms of its physical properties, aesthetic characteristics and stability.
Hyoscyamine (FIG. 1) also known as daturine is a tropane alkaloid. It is a secondary metabolite found in certain plants of the Solanaceae family, including henbane (Hyoscyamus niger), mandrake (Mandragora officinarum), jimsonweed (Datura stramonium), tomato (Solanum lycopersicum) and deadly nightshade (Atropa belladonna). It is the levorotary isomer of atropine (third of the three major nightshade alkaloids) and thus sometimes known as levo-atropine.
Hyoscyamine is an antagonist of muscarinic acetylcholine receptors (antimuscarinic). It blocks the action of acetylcholine at parasympathetic sites. It is used to provide symptomatic relief to various gastrointestinal disorders including spasms, peptic ulcers, irritable bowel syndrome, diverticulitis, pancreatitis, colic and cystitis. It has also been used to relieve some heart problems, control some of the symptoms of Parkinson's disease, as well as for control of respiratory secretions in palliative care. It may be useful in pain control for neuropathic pain treated with opioids as it increases the level of analgesia obtained. Several mechanisms are thought to contribute to this effect. The closely related drugs atropine and scopolamine and other members of the anticholinergic drug group like cyclobenzaprine, trihexyphenidyl, and orphenadrine are also used for this purpose. When hyoscyamine is used along with opioids or other anti-peristaltic agents, measures to prevent constipation are especially important given the risk of paralytic ileus.
U.S. Pat. No. 5,464,632 describes a tablet prepared by dry blending an active ingredient with a granulated carbohydrate, to form a composition, which is compressed to form the tablet.
U.S. Pat. No. 6,149,938 discloses a process for making a granulate composition suitable for the preparation of an oral solid form that can disintegrate rapidly inside the buccal cavity.
U.S. Pat. No. 7,282,217 discloses a rapidly disintegrating tablet comprising a compressed granulate containing hyoscyamine, directly compressible spray-dried mannitol; and directly compressible microcrystalline cellulose. It also discloses a rapidly disintegrating tablet comprising an active ingredient, a water soluble, directly compressible carbohydrate, and a water soluble, directly compressible filler.
U.S. Pat. No. 7,425,341 discloses a method of producing a rapidly disintegrating tablet of hyoscyamine. The method comprises wet granulating a mixture comprising a directly compressible water soluble carbohydrate; a, water insoluble filler, hyoscyamine sulfate, and a solvent, and compressing the granulate to produce the tablet.
U.S. Pat. No. 8,840,924 discloses a rapidly dissolving, taste-masked hyoscyamine pharmaceutical composition comprising a hyoscyamine-resin complex, one or more amorphous sugars and a compressible, free-flowing, pharmaceutical, taste-masking excipient.
There are number of medications or pharmaceutical compositions available for hyoscyamine sulfate. NuLev®, chewable melt tablets of hyoscyamine sulfate, marketed by Alaven Pharmaceuticals in USA contained inactive ingredients lactose monohydrate, magnesium stearate, mannitol USP, peppermint flavor, starch and stearic acid. Anaspaz®, the orally disintegrating tablets of hyoscyamine sulfate, marketed by B.F. Ascher and Co., Inc. in USA contained inactive ingredients lactose, magnesium stearate, mannitol, sorbitol, pregelatinized starch and stearic acid.
The stability of hyoscyamine sulfate in oral dosage form is still a matter of concern due to the presence of impurities in the formulation. As reported in the literature that hyoscyamine sulfate contains seven impurities, viz., DL-tropic acid, 7-hydroxyhyoscyamine, 6-hydroxyhyoscyamine, scopolamine, norhyoscyamine, apoatropine and littorine. The mechanism of formation of each impurity is different and based on some scientific principles. Impurities are formed because of gradual degradation of active ingredient in the composition. Usually, the degradation is chemical, i.e., active ingredient is altered at a chemical level thereby affecting its activity as well as the overall stability and usefulness of the composition. The stability issues generally adversely affect the costs of commercializing the composition. Hence, there is a need to develop a storage-stable dosage form of hyoscyamine sulfate with increased shelf-life and method of preparing thereof.